9Beta-hydroxy-5-methyl-6,7-benzomorphans

ABSTRACT

N-Substituted -9 Beta -hydroxy-5-methyl-6,7-benzomorphans have been found to possess potent narcotic agonist and/or antagonist activity. In particular, the compound 2&#39;&#39;-hydroxy-2cyclopropylmethyl-5-methyl-9 Beta -hydroxy-6,7-benzomorphan has been found to possess potent narcotic agonist and antagonist activity. These compounds are prepared by total synthesis and are not derived from opium alkaloids.

United States Patent Monkovic et a1.

9BETA-HYDROXY-5-METHYL-6,7-

BENZOMORPHANS Inventors: Ivo Monkovic, Candiac; Michel Saucier, Dorval, both of Canada; Thomas Alfred Montzka, Manilus, NY.

Assignee: Bristol-Myers Company, New York,

Filed: Sept. 26, 1973 Appl. No.: 400,861

Related U.S. Application Data Continuation-impart of Ser. No. 301,049, Oct. 26, 1972, abandoned.

U.S. CL, 260/293.54; 260/240 K; 260/DIG. 13',

424/267 Int. Cl C07d 39/00 Field of Search 260/293.54, DIG. 13

References Cited UNITED STATES PATENTS 5/1967 Kupchan et a1 260/294.7 10/1969 Ziering 260/2947 1 June 24, 1975 3,513,169 5/1970 Robinson et a1 260/2947 3,514,463 5/1970 Robinson et a1. 260/2947 3,632,591 1/1972 Albertson et a1. 260/29154 3,639,407 2/1972 Clarke et a1. 260/29354 3,639,410 2/1972 Albertson et al. 260/29354 3,647,806 3/1972 Cross 260/293.54 3,700,734 10/1972 Robinson et a1 260/293.54

OTHER PUBLICATIONS May et al., J. Org. Chem. 26, 1621-1624 (1961). May et al., J. Org. Chem. 26, 4536 (1961).

Primary Examiner-G. Thomas Todd Attorney, Agent, or FirmRobert E. Havranek [57] ABSTRACT 6 Claims, No Drawings 9 BETA-HYDROXY--METHYL-6,7-

BENZOMORPHANS CROSS-REFERENCE TO RELATED APPLICATION This application is a continuation-in-part of copending application Ser. No. 301.049. filed Oct. 26. I972, now abandoned.

BACKGROUND OF THE INVENTION in which R' is H or methyl and R is methyl or phenethyl as being moderate to weak analgetics.

B. Everette May. James Murphy and .l. Harrison Ager. J. Org. Uzem. 25, 1386 (I960) report compounds having the formula in which R is methyl or phenethyl and R is H or methyl as being potent analgetics.

C. Everette May. Hiroshi Kugita and J. Harrison Ager, J. Org. Chem. 26. I62I (1961) report compounds having the formula in which R is methyl or phenethyl, R' is methyl or H, R is H. OH or methoxy as producing varying degrees of analgesia.

D. Everette May. Colin Chignell and J. Harrison Ager, J. Med. Chem. 8. 235 (1965) report compounds having the formula in which R' is H or methyl and R is methyl as possessing analgetic activity.

E. Everette May and Hiroshi Kugita, J. Org. Chem.,

26, I954 (196I) report the compound having the formula in which R is methyl or phenethyl, R is H or methyl and R is H or acetyl as having analgetic activity.

G. Everette May and Seiichi Sato, J. Org. Chem. 26, 4536 (1961) report compounds having the formula -CH 33 ca in which R- is H or methyl, R is methyl or ethyl, R" is methyl or ethyl and R is H or acetyl as possessing analgetic activity.

H. N. B. Eddy and E. L. May published a review of 6.7-benzomorphans in Synthetic Analgetics, Pergamon Press (1966).

SUMMARY OF THE INVENTION Compounds having the formula wherein R is selected from the group comprising CH- ,C CH, CH- 1CH=CH- and (Iower)alkenyl in which R is H or CH,-;. R is selected from the group comprising H, (lower)alkyl.

O O n 1 I 41-0-90, (lower)acyl, -COI,

u I -c and 4Q O R is H, (lower)acyl, trichloroacetyl or cinnamoyl; R" is H, CH3, C2H5 N=C2H7, Or CH C CH, or a pharmaceutically acceptable acid addition salt thereof are analgetic agents, narcotic antagonists or intermediates in the preparation of such agents.

DISCLOSURE OF THE INVENTION xxxx wherein R is selected from the group comprising CH C CH, CH CH=CH- h 6 Ja -6 -c11 -Cli -CH=CH -c 2 n e-q and (lower)a]kenyl in which R is H or CH3. R is sea lected from the group comprising H, (lower)alkyl,

i i 4Q, (lower)acyl, -CI

O it 1 it 4Q, -CH -CH -c-cl:-c:a

R is H, (lower)acyl, trichloroacetyl or cinnamoyl; R" is H, CH3, CgHa, NC3H7, OI -CH- C CH; or a pharmaceutically acceptable acid addition salt thereof.

Drug abuse by thrill-seeking youth or by people looking for an escape from the realities of every day life has become more and more common place in our present society. One class of widely abused drugs are the narcotic analgetics such as codeine, morphine. meperidine. etc. It is because of the high addictive potential of these agents that much time and money are being expended by the pharmaceutical industry and by governments to try and discover and develop new nonaddicting analgetics and/or narcotic antagonists.

It was therefore an object of the present invention to find new and novel compounds that have these characteristics.

and

It was further an object of the present invention to develop a method of synthesis that would not be dependent upon opium alkaloids as starting materials and yet would be commercially feasible.

The objectives of the present invention have been achieved by the provision of the compounds of formula L and by their total synthesis from the readily available starting material 7-methoxy-3.4-dihydro-2[ ill I- naphthalenone (I).

The compounds of the instant invention have the basic benzomorphan nucleus which is numbered and represented by the following plane formula Although there are three asymetric carbons (asterisks) in the benzomorphan molecule, only two diastereoisomeric (racemic) forms are possible, because the iminoethano system, attached to position I and 5, is geometrically contained to a cis-(l,3-diaxial)-fusion. These racemates can therefore differ only in the configuration of carbon 9. The only variable will be the cis and trans relationship of the 9-hydroxy compound to the iminoethano system. When in the compounds of the present invention the 9-hydroxy is trans to the iminoethano system, we have the Qa-hydroxybenzomorphans. When the 9-hydroxy is cis to the iminoethano system, we have the 9B hydroxybenzomorphans.

The use of a graphic representation of a benzomorphan is meant to include the d! racemic mixture and the resolved d and I isomers thereof The compounds of the present invention. the 9B-hydroxybenzomorphans, can exist as two optical isomers, the levorotatory and dextrorotatory isomers. The optical isomers can be graphically illustrated as:

9 B- H ydroxybenzomorphan and )alkyl" is defined us an alkyl radical containing l to 6 carbon atoms. (Lower)alkyl" is defined as a hydrocarbon radical of 3 to 7 carbons containing one double bond. The term (lower)acyl" is an acyl radical of 2 to 6 carbon atoms, e.g., acetyl. propionyl, isobutyryl. etc. The term pharmaceutically acceptable acid addition salt" is defined to include all those inorganic and organic acid salts of the compounds of the instant invention, which salts are commonly used to produce nonby mixing the compounds of formula L with hydrochloric, sulfuric nitric, phosphoric. phosphorous. hydrobromic. maleic. malic, ascorbic. citric or tartaric. pamoic. lauric. stearic, palmitic, oleic. myristic. lauryl sulfuric. napthalinesulfonic, linoleic or linolenic acid, fumaric, and the like.

The compounds of the instant invention are prepared by a total synthesis comprising multiple steps Surprisingly, the synthesis is efficient and appears commertoxic salts of medicinal agents containing amine funcl0 cially feasible. The process is outlined in Charts l and tions. Illustrative examples would be those salts formed IXa XIIa

NH Example 13 O cn o 0 Example 1 o CH3 H CH3 9? 1 ca 9/ 3 N E 1e 3 xamg cn c n o c11 0 0 G) 2-c a 3 \CH3 m Iv 0H c11 0 OH VIa XIa

0H Example 15 i l. -XIIa tartrate CHART II v Example 7 5 N-CH3 CH H2 -9 3 XX se N CH N-E-C H Exam ple 9 (I? 2 5 OH O-C-CH 3 CH CH CH3 CH 9 VIb ff VIIIb Example 11 N f 3 CH cu 3 IX!) a XI!) N-cH OH an 3 3 XIIb A preferred embodiment is the compounds having a 1 a the formula I 0-, i L-, 9 K

2 "R; R o OR o xxx ll r'-\ 3 x 0-, 0 N-CH -CH wherein R is selected from the group comprising CH2-CH I CH. CH2CH=CH 0 CH 6 -CH CH=C: -cH }-,R 42: 6, 0111 0 CH H II CB -C--C, CH 0-CH QCH -C: CH} ()0 (QB wa Q, -CH CH=CH, -cn Q 3 l CH R is selected from the group comprising H, (lower)acyl. trichloroacetyl and cinnamoyl; R is H, CH C H -0 -G N c,.,H,, CH CH=CH CH- -C s CH; or a pharmaceutically acceptable acid addition salt thereof. and Cm alkenyl in which R is H or CH;,; R is selected A more preferred embodiment is the compounds of from the group comprising H, (lower)alkyl, (lower)aformula XXXX wherein R is CH C E CH, CH cyl, -CH=CH- CH 6 -cn ca=c -cH }-R in which R is H or CH R is H. CH;;.

i l i and R is H or acetyl. R" is H, CH or C H or a pharmaceutically acceptable acid addition salt thereof.

Another more preferred embodiment is the compounds of formula XXXX wherein R' is or CH CH=CH R is H. CH or R is hydrogen or acetyl, R is H or methyl; or a pharmaceutically acceptable acid addition salt thereof.

Most preferred embodiments are: I The compound of formula XXXX wherein R is 5 -cH l R is H, R" is H, and R is H; or the hydrochloric salt thereof.

2. The compounds of formula XXXX wherein R is R is H, R is CH;,. and R is H; or the hydrochloric salt thereof.

The processes for the preparation of the compounds of the instant invention are new and novel and also constitute preferred embodiments.

A preferred embodiment of the present invention is the process of preparing compounds having the formula H0 R L wherein R is selected from the group comprising CH C I CH, CH CH=CH,

CH -CH -CH=C -cn j-n cu O ma 2], CH2-CH=?JH,

and C alkenyl in which R" is n or CH R" is H, CH C2H3 N C;;H 7. 0r -C I CH; R is H. (lower)acyl, trifluoroacetyl or cinnamoyl; which process comprises the consecutive steps of A. treating the compound having the formula R3 7 R 0 5 0R5 CH3 XXXXIII in which R is (lower)alky1, R and R are as defined above, with an alkylating or acylating agent having the formula in which W is a radical selected from the group comprising C I CH. CH=CH- and C alkenyl in which R" is H or CH;;. Z is carbonyl or CH and X is chloro, bromo or iodo, in an inert organic solvent in the presence of an appropriate base to produce the compound having the formula n- (z -w 611 XXXXIV in which R, R", R", Z and W are as defined above;

B. treating compound XXXXIV with lithium aluminum hydride when (Z) is carbonyl in an inert organic solvent, to produce the compound having the formula CH3 XXXXV in which R R. R and W are as defined above; and

C. cleaving the ether function of compound XXXXV or XXXXIV in which Z is CH by treatment with an agent selected from the group comprising Na S-C H hydrobromic acid. boron tribromide or pyridine hydrochloride.

For the purpose of this disclosure. the term inert organic solvent means an organic solvent that does not participate in the reaction to the extent that it emerges unchanged from the reaction. Such solvents are methylene chloride. chloroform, dichloroethane, tetrachloromethane. benzene. toluene, ether, ethyl acetate, xylene, tetrahydrofuran, dioxane, dimethylacetamide, dimethylforamide, and the like when an acid halide is employed. When an alkylation reaction is being performed. the inert solvent used may also include (lower- )alkanols such as methanol, ethanol. n-propanol, isopropanol and the like. The term appropriate base is an organic tertiary amine which is a tertiary amine commonly employed as a proton acceptor in acylation reactions. Such amines are tri(lower)alkylamines. e.g., trimethylamine, triethylamine, and the like, pyridine, dimethylaniline. N-methylpiperidine. and the like.

Another preferred embodiment is the process for preparing compounds having the formula R5 r R70 5 OR) XXXXa wherein R is selected from the group comprising CH- C CH. CH CH=CH- xxxxnr in which R is (lower)alkyl and R and R are as defined above; with an alkylating agent having the formula in which R is as above and X is chloro, bromo, or iodo, in an inert organic solvent in the presence of an appropriate base to produce the compound having the formula 3 XXXXIVa in which R, R, R and R are as above; and

B. cleaving the ether function of compound XXXXlVa by treatment with NaSC- H,-,, boron tribromide or pyridine hydrochloride.

All of the compounds of the preferred embodiments herein are novel and valuable for their properties as analgesic and/or narcotic antagonist agents, or as intermediates in the preparation of compounds having these biological activities.

In particular, the compounds having the formula XII are those which possess the most desirable properties; i.e., analgesic and/or narcotic antagonist properties. Some of these compounds also possess antitussive activity, a property generally inherent with analgetic activity.

It is well known in the narcotic analgesic prior art that it is possible for some compounds to possess both agonist and antagonist properties. An agonist is a compound that imitates a narcotic analgesic and possesses analgetic qualities. An antagonist is a compound that counteracts the analgetic and euphoric properties of a narcotic analgetic. It is possible for a compound to have both properties. A good example of such a compound is cyclazocine.

In vivo testing was conducted on the compounds designated herein as dl-Xlla, l-Xlla and dl-Xllc in the form of their respective soluble salts to determine their agonist and/or antagonist properties. Table I represents the results of the experiments. The figures reported are the number of milligrams/kilogram of body weight of compound that produced an agonist or antagonist effect in 50% of the mice and rats so tested (ED-,0).

TABLE I E sn (mg/kg)" Agonist Activity Antagonist Activity Mouse Morphine Phenylquinone Oxymorphone 2 Oxymorphone 3 Antagonism writhing Straub Tail Narcosis Rat Tail Flick Test Compounds SC PO SC PO SC PO SC P0 dl-Xlla 0.62 3.2 1.5 ND. ND. N.D. 0.26 ND. l-XIla 0.1] ND. 0.60 N.D. 0.15 N.D. 0.104 N.D. dl-Xllc 0.30 ND. 1.01 N.D. 0.1 ND. 0.22 N.D.

TABLE 1 Continued BB) (mg/kg) Agonist Activity Antagonist Activity Mouse Morphine Phenylquinone Oxymorphone 2 Oxymorphone Antagonism writhing Straub Tail Narcosis Rat Tail Flick Test Compounds SC PO SC PO SC PO SC PO Pentazocine 4.9 36 12.0 187 10.1 90 12.2 82.2 Nalorphine 0.77 1.14 64 0.58 5.4 0.38 22.1 Levallorphan 26.3 N.D. 0.29 46 0.32 5.4 0.086 12.6

(poor dose responsel Cyclazocine 0.047 0.81 24 0.12 2.7 0.040 3.7 Naloxone 40 N.D. 0.17 13.1 0.02 0.95 0.010 2.7

' A per cent reduction in number of phenylquinone induced writhings (Siegmund, E. A. et al.. Proc. Soc. Biol. & Med. 95.

2 Antagonism of Straub Tail induced by oxymorphone (2 mgJkg. so.) in 50 per cent of mice. Antagonism of righting reflex loss induced by oxymorphone (1.5 mgJkg. sc.) in 50 per cent of rats. A 50 per cent reduction of analgesic effect induced by morphine (15 mgJkg. sc.) as measured by the rat tail flick procedure (Harris. L. S. and Pierson. A. K.. J. Pharmacol. 8L Expt.

N.D.-Not done. 5 All weights reported are corrected to read in terms of the free base.

It is apparent from the testing that the compounds have potent agonist and antagonist activity. The normal parenteral dosage range of the compounds of the present invention in adult humans is about 0.25 to 10 mg. three to four times a day. Orally the dose is in the range of about 2 to 50 mg. three or four times a day.

It has been reported in the literature that the compound haloperidol, 4l4-(p-chlorophenyl)-4-hydroxypiperidino}-4'-fluorobutyrophenone (Merck Index, 8th Edition. p. 515) has found some experimental use in the alleviation of narcotic addiction withdrawal symptoms. It is therefore a preferred embodiment of the present invention to combine haloperidol with the narcotic antagonists of the instant invention to produce a product not only preventing narcotic abuse, but at the same time providing supportive therapy in the absence of opiates.

Haloperidol is commonly administered orally in 0.5 to 5.0 mg. two or three times daily depending upon the severity of the illness. A dose of haloperidol in this range would be administered contemporaneously with an effective dose of the narcotic antagonist to produce the desired result.

Other combinations would include the narcotic antagonists in combination with anti-anxiety agents such as chlorodiazepoxide and diazepam. or phenothiazines like chlorpromazine. promazine or methotrimeptrazine.

EXAMPLE 1 3.4-Dihydro-7-methoxy- 1 -methyl- 2( 1H)naphthalenone (ll) Therap, I43, 141; 1964).

dissolved in 50 ml. of benzene. The mixture was refluxed for one hour and 5 ml. of water was collected in a Dean-Stark apparatus. The mixture was cooled and added slowly to 0.5 mole of methyl iodide dissolved in 300 ml. of benzene. The resulting mixture was refluxed for 3 hours. Then 200 ml. of water was added to the reaction and refluxing was resumed. After 30 minutes the mixture was cooled, the benzene layer was separated, washed with water, followed by water saturated with sodium sulfate and evaporated to dryness. The residue was distilled to give ll. The infrared (IR) and Nuclear Magnetic Resonance (NMR) spectra were consistent with the structure.

EXAMPLE 2 tco n) 2 C CH -CH N III A solution of 7-methoxy- 1 -methyl- 3,42(1H)naphtha1enone (0.12 m) ll in benzene (40 ml) was added to a refluxing suspension of sodium hydride (0.14 m) in benzene ml). After one hour re flux, this mixture was treated with a solution of 2- benzylmethylaminoethylchloride (0.12 m) in benzene (100 ml) and heated at reflux for 18 hrs. The reaction mixture was washed with water, then extracted into dilute hydrochloric acid. Neutralization of the acid extract with ammonium hydroxide and extraction with ether afforded an oil which was converted to an oxalate salt (78%); mp l37139C.

Anal. calcd. for C- H NO .C- H O,: C, 67.43; H. 6.84; N, 3.28. Found: C, 67.25; H, 7.05; N, 3.50.

EXAMPLE 3 2-Benzyl-2 '-methoxy-5-methyl-9-oxo-6,7- benzomorphan methobromide (1V) Compound III was converted to its hydrobromide salt by treatment with sodium hydroxide solution. isolation by extraction with ether and subsequent treatment with HBr. This hydrobromide salt (0.21 m) was dissolved in 450 ml acetic acid and slowly treated with a solution of bromine (l 1.2 ml) in 50 ml acetic acid and stirred for one-half hr. This was diluted with two liters of Skellysolve B" (essentially n-hexane) and cooled under nitrogen. The Skellysolve B layer was decanted from the gummy precipitate. This residue was partitioned between ether and water. This two phase system was basified with conc. ammonium hydroxide. The layers were immediately separated and the aqueous layer extracted with ether. Concentration of the ether extracts gave an oil. This oil was taken up in acetone and stirred several hours to give IV as a crystalline solid (76%).

EXAMPLE 4 o HBI CH O 0 l CH V 2.5-Dimethyl-2'-methoxy-9-oxo-6,7-benzomorphan EXAMPLE 5 VIa 2.5-Dimethyl-9B-hydroxy-2'-methoxy-6,7- benzomorphan hydrobromide (Via) A suspension of IV (0.04 m) in 200 ml ether was treated with 50 ml of a 2.5 m solution of isopropyl magnesium chloride in tetrahydrofuran. This mixture was EXAMPLE 6 IXa 5-Methyl-9/3-hydroxy-2 '-methoxy-6,7-benzomorphan (lXa) A mixture of Vla free base (0.031 m) and ml acetic anhydride was heated at 100 for 1 hour. The acetic anhydride was removed at reduced pressure. Treatment of the residue with sodium carbonate and extraction with methylene chloride afforded a quantitative yield of 2,4-dimethyl-2'-methoxy-9B-hydroxy- 6,7benzomorphan 9/3-acetate. This material was taken up in benzene 100 ml) and treated with potassium carbonate (5 g) and ethyl chloroformate (10 ml). This mixture was heated at reflux under nitrogen for 26 hrs. This mixture was treated with water. The benzene layer was separated and washed with dilute hydrochloric acid and saturated sodium chloride to afford after concentration a quantitative yield of 5-methyl-2'-methoxy- 2-carbethoxy-9B-hydroxy-6,7 benzomorphan 9B-acetate. This material was taken up in ethanol (250 ml) and treated with 30 g potassium hydroxide. This was heated at reflux under nitrogen for 90 hours. The ethanol was removed at reduced pressure. Treatment of the residue with 10% sodium bicarbonate and extraction with methylene chloride afforded 7.2 g. lXa Recrystallization from toluene gave analytically pure material (6.8 g 94%); mp l32.0l33.5 Anal. calc'd. for C HWNO C, 72.07; H. 8.21; N, 6.00. Found: C. 72.08; H. 8.03; N. 6.08.

EXAMPLE 7 2.5-Dimethyl-9-( spiro-B-epoxy )-2 -methoxy-6.7- benzomorphan (XX) N-CH I CH xx A solution of 2.5-dimethyl 2'-methoxy-9-oxo-6,7 benzomorphan (V) (0.05 m) in [25 ml dry dimethylsulfoxide was added to a 55% sodium hydride dispersion (0.] m) with stirring under nitrogen. To this mixture was added trimethyl-sulfonium iodide (0.1 m) with stirring. After stirring for 4 hrs. under nitrogen, the

mixture was diluted with water and extracted with methylene chloride. Drying and concentration of these extracts gave an oil which vpc analysis indicated to contain 87% B-isomer (XX), 67% of another product believed to be a-isomer and some starting ketone. Chromatography on alumina followed by crystallization from cyclohexane gave pure XX (64% yield of 95% isomer purity); mp 93-95C.

Anal. calcd. for CmHgrNOgZ C, 74.10; H. 8.16; N. 5.40. Found: C. 73.89; H. 8.30; N, 5.36.

EXAMPLE 8 9B-Hydroxy-2-methoxy-2,5 ,9a-trimethyl-6.7- benzomorphan hydrochloride (Vlb) A solution of 2,5-dimethyl-9-(spiro-B-epoxy)-2- methoxy-6,7-benzomorphan (XX) (0.028 m) in 75 ml tetrahydrofuran was added to a stirred suspension of lithium aluminum hydride (0.045 m) in 25 ml tetrahydrofuran (THF). This mixture was stirred at 25C for 16 hrs. and heated at reflux for 2 hrs. This mixture was cautiously treated with ml saturated sodium sulfate. The solids were removed by filtration and the filtrates concentrated to dryness. The residual oil was converted to a hydrochloride and crystallized from ethanol-ethyl acetate-water to give pure Vlb hydrochloride hydrate (86% yield); mp 1390-1430 C. Vpc (vapor phase chromatography) analysis on the free base indicated an isomer purity of 96%. Solution infrated spectra (CCL) at different concentrations shows only bonded OH indicating the B-OH configuration.

EXAMPLE 9 Preparation of 9B-Acetoxy-2-carbethoxy-5 .9a-dimethyl-2 '-methoxy- 6.7-benzomorphan (Vlllb) 9B-Hydroxy-2-methoxy-2.5.9a-trimethyl-6.7-

benzomorphan (Vlb) (0.022 m) was treated with 50 ml acetic anhydride and heated on a steam bath for 3 hr. After removal of the acetic anhydride at reduced pressure, the residue was treated with dilute sodium carbonate and extracted with benzene. Drying and evaporation of the benzene extracts yielded the acetoxy compound 9Bacetoxy-2,5.9a-trimethyl-2'-methoxy-6,7- benzomorphan (Vllb). A solution of this material in benzene was treated with 2.5 g potassium carbonate and 6.5 ml ethyl chloroformate (0.07 m) and heated at reflux for 16 hr. This mixture was cautiously treated with l 20 ml lN hydrochloric acid. The layers were separated and the aqueous layer was extracted with benzene. Drying and concentration of the combined benzene extracts gave title product (VIIIb) which was re crystallized from 95% ethanol; mp 87.5-88.5C. Anal. calcd. for C .,H ,-NO,-.: C, 66.46 H. 7.53; N. 3.88. Found: C. 66.18; H, 7.62; N. 3.75.

EXAMPLE 10 Preparation of 5.901-Dimethyl-9B-hydroxy-2-methoxy-6.7- benzomorphan (lXb).

A mixture of dimethyl-2 '-methoxy-6,7-benzomorphan (Vlllb (0.002 m). 2.5 g potassium hydroxide and 20 ml 95% 6 9,8-acetoxy2-carbethoxy-5,9a-

EXAMPLE 1 l O a 3 CH XIb 2-Cyclopropylmethyl-5 .9a-dimethyl-9/3-hydroxy-2 methoxy-6,7-benzomorphan Xlb A solution of 5,9-a-dimethy1-l lB-hydroxy-T- methoxy-6.7-benzomorphan (IXb) (0.005 m) in 25 m] methylene chloride and 7.5 ml triethylamine was treated with cyclopropylcarbonyl chloride (3 ml) with stirring. This mixture was stirred for l8 hours and then treated with dilute sodium carbonate. The layers were separated and the aqueous layer extracted with methylene chloride. Drying and concentration of the methylene chloride extracts gave Z-cyclopropylcarbonyl- 5,9oz-dimethyl-9B-hydroxy-2'-methoxy-6.7- benzomorphan (Xb) as an oil. This material was taken up in tetrahydrofuran (30 ml) and added to a stirred suspension oflithium aluminum hydride 1 .0g) in tetrahydrofuran (20 ml). After an 18 hour reflux period. this mixture was cautiously treated with 3 ml saturated sodium sulfate and warmed until solids were white. Removal of the solids by filtration and concentration of the filtrates gave an oil (Xlb) which was converted to its hydrobromide salt; mp 242-244C.

Anal. calcd. for C ,H ;NO .HBr: C. 59.68; H. 7.38; N. 3.66. Found: C. 59.31; H. 7.52; N. 3.35.

EXAMPLE l2 XIIb 2-Cyclopropylmethyl-5 .9a-dimethyl-2 ,9B-dihydroxy- 6,7-benzomorphan hydrogen fumarate (Xllb) Z-Cyclopropylmethyl-S ,9a-dimethyl-9B-hydroxy-2 methoxy-6,7-benzomorphan hydrobromide (Xlb) (0.00l3 m) was treated with l0 ml 48% hydrobromic acid and heated in an oil bath at l30l 33C under nitrogen for 20 minutes. This was cooled, basified with ammonium hydroxide and extracted with methylene chloride to give a tan foam which was converted to a crystalline fumarate in ethanol-ethyl acetate; mp 228-235C (decomp).

Anal. calcd. for C H NO C,H,O,: C, 65.49; H, 7.24; N. 3.47. Found: C. 65.34; H. 7.10; N, 3.44.

EXAMPLE 13 Z-Cyclopropylmethyl-l 1B-hydroxy-2methoxy-5- methyl-6,7-benzomorphan hydrobromide (Xla) Substitution in the procedure of example 1 1 for the 5.9a-dimethyl-1 1B-hydroxy-Z'-methoxy-6,7 benzomorphan used therein of an equimolar quantity of 9B-hydroxy-5-methyl-2'-methoxy-6,7 benzomorphan produced the title compound Xla; m.p. l99-200.5 C.

Anal. calcd. for C H NO .HBr: C, 58.69; H. 7.12; N. 3.80. Found: C. 58.76; H, 7.21; N. 3.72.

EXAMPLE l4 2-Cyc1opropylmethyl-2',9B-dihydroxy-5-methyl-6.7- benzomorphan (dl-Xlla) A solution of sodium thioethoxide (0.04 mole) and the free base of Xla (0.0022 mole) in 30 ml DMF (dimethylformamide) was heated at reflux under nitrogen for three hours. The DMF was removed at reduced pressure. The residue was treated with toluene and extracted with dilute hydrochloric acid. The acid extracts were made basic with sodium carbonate and extracted with methylene chloride to give an oil which glc (gasliquid chromatography) indicated to be about 60% product. Formation of the hydrochloride and several crystallizations from 95% ethanol gave pure Xlla hydrochloride; mp 235240C. decornp.

Anal. calcd. for C, H- NO- .HC1:C, 65.90; H. 7.81; N, 4.52. Found: C, 65.75; H. 8.17; N, 4.67.

EXAMPLE Resolution of dI-Xla into I-2-cyclopropylmethyl-9B-hydroxy-2'-methoxy-5- methyl-6,7-benzomorphan tartrate (I-Xla tartrate) A mixture of dI-Xla (0.0087 mole) and tartrate acid (1.4g) was dissolved in hot ethanol ml) and then cooled for crystallization. The crystals were collected and recrystallized from 15 ml ethanol to give pure I-Xla tartrate; mp 15l152C; [01],, -56 and [01], (Hg) -1 19(C 0.99. 95% ethanol).

Anal. calcd. for C,,.H -,NO .C,l-l,,0 C. 60.40; H, 7.14; N, 3.20. Found: C. 60.01; H. 7.46; N. 3.21.

EXAMPLE 16 l-2-Cyclopropylmethyl-2; 9B-dihydroxy-5-methyl-6.7-benzomorphan hydrochloride (I-Xlla) A solution of sodium thioethoxide (0.06 mole) and free base of I-Xla tartrate (0.0034 mole) in DMF ml) was heated at reflux for 3 hours. After removal of the DMF, the residue was treated with toluene and extracted with dilute hydrochloric acid. These acid extracts were basified with sodium carbonate and extracted with methylene chloride to give an oil with glc indicated to be about 63% product. This material was i purified by chromatography on silica gel with ethyl acetate as solvent. Formation of the hydrochloride and re crystallization from ethanol afforded pure l-Xlla HC]; mp 247252C decomp.; [01],, and 1 143" Hg)208 (C 0.921. 95% ethanol).

Anal. calcd. for C H- NO HCI: C, 65.90; H, 7.81; N, 4.52.

Found: C, 65.78; H, 8.09; N. 4.66.

EXAMPLE l7 2-Cyclobutylmethyl-5,9a-dimethyl-9B-hydroxy-2'- methoxy-6,7-benzomorphan (Xlc) Substitution in the procedure of example 11 for the cyclopropylcarbonyl chloride used therein of an equimolar quantity of cyclobutylcarbonyl chloride produced the title compound Xlc; m.p. 225- 229C. Anal. calcd. for C H NO HBr: C, 60.60; H, 7.63; N, 3.53. Found: C. 60.72; H. 7.76; N. 3.43.

EXAMPLE l8 2-Cyclobuty1methyl-5,9rx-dimethyl-2',9B-dihydroxy- 6,7-benzomorphan hydrochloride hydrate (Xlle) Substitution in the procedure of example 12 for the compound Xlb and fumaric acid used therein of equimolar quantities of compound Xlc and dry HCl gas produced the title compound Xllc; m.p. l49.5l54.5C.

Anal. calc'd. for C H NO HCLH O: C. 64.12; H, 8.50; N, 3.94. Found: C, 64.17; H, 8.47; N, 3.91.

EXAMPLE 19 2-Cyclobutylmethyl-9B-hydroxy-2-methoxy-5-methyl- 6,7-benzomorphan hydrobromide (Xld) Substitution in the procedure of example 11 for the cyclopropylcarbonyl chloride and compound lXb used therein of equimolar quantities of cyclobutylcarbonyl chloride and compound lXa produced the title compound Xld; m.p. 227.5-229.5C.

Anal. calcd. for CH|H27NO2.HB|': C. 59.68; H, 7.38; N, 3.66. Found: C. 59.72; H. 7.15; N, 3.57.

EXAMPLE 2O 2 -Cyclobutylmethyl-2 ',9B-dihydroxy-5-methyl-6,7- benzomorphan hydrobromide (Xlld) Substitution in the procedure of example 12 for the compound Xlb used therein of an equimolar quantity of compound Xld produced the title compound Xlld', m.p. 252258C.

Anal. calc'd. for C,,,H- -.NO .HBr: C. 58.69; H. 7.12; N, 3.80. Found: C. 58.74; H, 7.24; N. 3.72.

EXAMPLE 2 1 2-Allyl-2 ,9B-dihydroxy-5-methyl-6.7-benzomorphanhydrobromide (Xlle) Substitution in the procedure of example 12 for the compound Xlb therein of an equimolar quantity of compound Xle produced the title product Xlle; m.p. 23l234C.

Anal. calcd. for C,.;H ,NO- .HBr: C, 56.47; H, 6.52; N, 4.12. Found: C. 56.20; H, 6.50; N, 3.81.

EXAMPLE 22 2 .5-Dimethyl-9a-ethyl-9,B-hydr0xy2'-methoxy-6,7- benzomorphan fumarate (Vlf) CHO (ll-I C H OH VIf A suspension of IV (0.025 mole) in THF (50 ml) was treated with a solution of vinyl magnesium bromide (0.075 mole) in the THF (80 ml). This mixture was stirred for hours. The reaction mixture was treated with saturated ammonium chloride solution (100 ml). The layers were separated and the aqueous layer extracted with THF. The THF extracts were washed with saturated sodium chloride, dried and concentrated to give XXI 1 1.2 g) as a viscous oil. This oil was hydrogenated in ethanol using Pd (OH) /C as catalyst to give Vlf. The fumarate salt was prepared and crystallized from n-propanol; mp l75l76C.

Anal. calc'd. for C,;H- ,-,NO .V2C H,0,: C, 68.44; H, 8.16; N, 4.20. Found: C, 67.53; H, 8.23; N, 4.08; H 0, 0.96.

EXAMPLE 23 9a-Ethyl-9B-hydroxy-2'-methoxy-5-methyl-6,7- benzomorphan hydrobromide (lXf) Substitution in the procedure of example 6 for the compound Vla used therein of an equimolar quantity of compound Vlf produced compound lXf; m.p. 168l69C.

Anal. calcd. for C H NO- HBr: C, 56.14; H, 7.07; N, 4.09. Found: C, 56.11; H, 7.11; N, 4.18.

EXAMPLE 24 2-A1lyl-9a-ethyl-9B-hydroxy-2'-methoxy-5-methyl- 6,7benzomorphan hydrogen fumarate (Xlf) Substitution in the procedure of example 50 for the compound lXa and acetonitrile used therein of equimolar quantities of compound lXf and ethanol produced the title product Xlf; m.p. l23.5125.5C. Anal. calcd. for C,t,.H ;NO .C,H,O,: C, 66.16; H, 7.48; N, 3.36.

Found: C, 66.34; H, 7.83; N, 3.17.

EXAMPLE 25 2-allyl-9a-ethyl-2 ,9B-dihydroxy-5-methyl-6,7- benzomorphan fumarate (Xllf) Substitution in the procedure of example 14 for the compound Xla used therein of an equimolar quantity of compound Xlf produced the title compound Xllf; m.p. 252257 (decomp.).

Anal. calcd. for C ,,H -,NO V2C,H,O,: C, 69.54; H, 7.88; N 3.82. Found: C, 69.42; H, 8.08; N, 3.82.

EXAMPLE 26 2-Cyclopropylmethyl-9a-ethyl-9B-hydroxy-2'- methoxy-5-methyl-6,7-benzomorphan hydrogen fumarate (Xlg).

Substitution in the procedure of example 1 l for the compound lXb used therein of an equimolar quantity of lXf produced the title compound Xlg as the hydrogen fumarate containing one-half mole of n-propanol; m.p. l43-144C.

Anal. calcd. for Cz|rH- NO .C H,0 .VzC;,H,.0: 66.55; 66.55; H, 8.08; N, 3.03. Found: C, 66.38; H, 8.02; N, 2.87.

EXAMPLE 27 2-cyclopropylmethyl-9methyl-2,9l3-dihydroxy-5- methyl-6,7-benzmorphan hydrogen fumarate (Xllg) Substitution in the procedure of example 14 for the compound Xla used therein of an equimolar quantity of Xlg produced the title compound Xllg; m.p. 245-253C. (decomp.).

Anal. calc'd. for C ,,H ;NO .C,H O C, 66.16; H, 7.48; N, 3.36. Found: C, 65.94; H, 7.73; N, 3.31.

EXAMPLE 28 EXAMPLE 29 2-Cyclobutylmethyl-9a-ethyl-2 ,9B-dihydroxy-5- methyl-6,7-benzomorphan fumarate (Xllh) Substitution in the procedure of example 14 for the compound Xla used therein of an equimolar quantity of compound Xlh produced the title compound Xllh in 81% yield; m.p. 23524lC.

Found: C. 70.96; H. 8.62; N, 3.56.

EXAMPLE 3 .4-Dihydro-7-methoxy- 1 -methyl- 1 (2,2- dimethylaminoethyl)-2[ 1 H lnaphthalenone hydrobromide (Illa) Substitution in the proceudre of example 2 for the 2- benzyl-2-methylaminoethylchloride used therein of an equimolar quantity of 2.2-dimethylaminoethyl chloride produced the title compound llla.

EXAMPLE 31 2,S-Dimethyl-Z'-methoxy-9-oxo-6,7-benzomorphan methobromide (lVa) Substitution in the procedure of example 3 for the compound [II used therein of an equimolar quantity of compound llla obtained in example 2 produced the title product lVa.

EXAMPLE 32 9a-allyl-2-methoxy-2.5 dimethyl-9B-hydroxy-6.7- benzomorphan methobromide (XXla) Substitution in the procedure of example 22 for the compound 1V and the vinylmagnesium bromide used therein of equimolar quantities of compound lVa and allyl magnesium bromide produced the title compound XXla.

EXAMPLE 33 9aallyl-2 '-methoxy-2.5-dimethyl-9Bhydroxy-6.7- benzomorphan (Vlk) EXAMPLE 34 9ot-Allyl-9B-hydroxy-5-methyl-2"methoxy-6.7-

benzamorphan hydrogen fumarate (lXk) Substitution in the procedure of example 6 for the compound Vla used therein of an equimolar quantity of Vlk produced the title product lXk', m.p.

Anal. calcd. for C H ;,NO 'C H.O C. 64.76; H, 6.94; N. 3.60. Found: C. 64.11; H. 7.23; N, 3.57; H O. 0.55.

EXAMPLE 2,9a-Diallyl-9B-hydroxy-2'-methoxy-5-methyl-6.7- benzomorphan hydrogen fumarate (Xlk) Substitution in the procedure of example 50 for the compound [X21 and acetonitrile used therein of an equimolar quantity of compound lXk and ethanol produced the title compound Xlk in 90% yield; m.p. l32135C.

Found: c. 66.97; H. 7.48; N. 3.39.

EXAMPLE 36 2.9a-Diallyl-2 '.9B-dihydroxy-5-methyl-6.7- benzomorphan hydrogen fumarate (Xllk).

Substitution in the procedure of example 14 for the compound Xla used therein of an equimolar quantity of compound Xlk produced the title product Xllk in 69% yield; m.p. 2l7223C. (decomp.).

Anal. calcd. for C,..H -,N0 -C.H.o.; C. 66.49; H, 7.04; N, 3.37. Found: C, 65.57; H, 7.19; N. 3.18; H O. 0.85.

EXAMPLE 37 9a-allyl-2-cyclobutylmethyl-9B-hydroxy-2-methoxy- 5-methyl-6,7-benzomorphan hydrogen fumarate (Xlj) Substitution in the procedure of example 1 l for the compound lXb and cyclopropylcarbonyl chloride used therein of an equimolar quantity of compound lXk and cyclobutylcarbonyl chloride produced the title compound Xlj in 89% yield; l79l80C.

Anal. calcd. for C H No- 'C H on C, 68.25; H, 7.71; N, 3.06. Found: C. 67.85. H. 7.79; N. 2.97.

EXAMPLE 38 9a-A1lyl-2-cyclobutylmethyl2.9B-dihydroxy-5- methyl-6,7-benzomorphan (Xllj) Substitution in the procedure of example 14 for the compound Xla used therein of an equimolar quantity of Xlj produced the title compound in 88% yield; m.p. 203-204C.

Anal.ca1cd. for C'ZIHZHNOZ'CJHJOJ: C, 67.70; H, 7.50; N, 3.16. Found: C. 67.42; H, 7.72; N, 3.51.

EXAMPLE 39 9a-Allyl-2-cyclopropylmethyl-9/3-hydroxy-2 methoxy-5-methyl-6,7-benzomorphan hydrogen fumarate (Xlm) Substitution in the procedure of example 1 l for the compound lXb used therein of an equimolar quantity of compound lXk produced the title compound Xlm in 76% yield; m.p. 139l41C.

Anal. calcd. for C;.H...N0. C.H.0.; C, 67.70; H, 7.50; N, 3.16. Found: C. 67.61; H. 7.50; N. 3.16

EXAMPLE 40 9a-Allyl-2-cyclopropylmethyl-Z',9B-dihydroxy-5- methyl-6.7-benzomorphan hydrogen fumarate (Xllm) Substitution in the procedure of example 14 for the compound Xla used therein of an equimolar quantity of Xlm produced the title product Xllm in 87% yield; mp. 23524lC.

Anal. calcd for C:|.H .-NO .-C,H.O;: C. 67.1 1; H. 7.28; N. 3.26. Found: C. 66.75; H. 7.55; N, 3.19

EXAMPLE 41 9B-Hydroxy-2'-methoxy-5-methyl-9a-propyl-6.7- benzomorphan hydrogen fumarate (lXn) Hydrogenation of lXk using 5% Pd/C as a catalyst in ethanol produced the title product as the hydrogen fumarate lXn in a yield of mp. l77183C.

25 Anal. calc'd. for C,,-H ;,NO C H;O C. 64.43; H. 7.47; N. 3.58. Found: C. 64.l6; H, 7.46; N. 3.42.

EXAMPLE 42 2-Allyl-9B-hydroxy-2-methoxy-5-methyl-Qa-propyl- 6.7-benzomorphan hydrogen fumarate (Xln) Substitution in the procedure of example 24 for the compound lXf used therein of an equimolar quantity of compound IXn produced the title compound Xln in 80% yield; rn.p. l65l66C.

Anal. calcd for CZUHQHNOQ'CJH4O4I C. 66.80; H. 7.71; N. 3.25. Found: C. 66.49; H. 7.91; N. 3.23.

EXAMPLE 43 2-Allyl-2 9B-dihydroxy-5-methyl-9a-propyl-6.7-benzomorphan hydrogen fumarate (Xlln) Substitution in the procedure of example l4 for the compound Xla used therein of an equimolar quantity of compound Xln produced in 66% yield the title compound Xlln; m.p. 2l5222C.

Anal. calcd. for C..,H. .-No,-c.H.o.; C, 66.16; H, 7.48; N. 3.36. Found: C, 65.81; H, 7.72; N, 3.40.

EXAMPLE 44 l-Z-Cyclopropylmethyl-Z ',9B-dihydroxy-5-methyl-6.7- benzomorphan diacetate l-Xlla free base (0.00l mole) was dissolved in 2 ml of acetic anhydride and 0.16 g of pyridine and refluxed for'l hour. The solvents are evaporated in vacuo, the residue dissolved in ether and the ether solution washed with dilute ammonium hydroxide solution. The ether layer is dried over sodium sulfate, filtered and evaporated in vacuo to dryness to yield the title product.

EXAMPLE 45 1-2-Cyclopropylmethyl-9B-hydroxy-2 -methoxy-- methyl-6,7-benzomorphan acetate l-Xla free base (0.00] mole) is dissolved in 1 ml of acetic anhydride and 0.08 ml of pyridine and refluxed for 1 hour. The solvents are evaporated in vacuo, the residue dissolved in ether and the ether solution washed with dilute ammonium hydroxide solution. The ether layer is dried over sodium sulfate. filtered and evaporated in vacuo to dryness to yield the title product.

EXAMPLE 46 I-Z-Cyclopropylmethyl-Z .9B-dihydroxy-5-methy1-6,7- benzomorphan 9B-monoacetate l-acetate (0.001 mole) obtained in example 45, dissolved in 5 ml of methylene chloride, is added with stirring to a cooled solution (l0C) of B Br (0.002 mole). The ice bath is removed and the reaction mixture left at room temperature for 30 minutes. The mixture is poured into crushed ice and concentrated ammonium hydroxide and extracted with chloroform. After drying over sodium sulfate and evaporation of the solvent, a residue of title product is obtained.

E XA MPLE 4 7 2-Cyclopropylbutyl-2 '.9,B-dihydroxy-5 .9a-dimethyl- 6,7-benzomorphan 2-(4-nicotinoate) To a solution of 0.002 mole of compound Xllc free base in 3 ml of pyridine is added 0.002 mole of 4- nicotinoyl chloride hydrochloride. The mixture is refluxed for 1 hour and the solvents evaporated. The residue is partitioned between ether and dilute ammonium hydroxide. the ether layer separated, washed with wa ter. dried over anhydrous sodium sulfate. filtered and evaporated in vacuo to produce the desired title nicotinoyl ester.

EXAMPLE 48 l-2-Cyclopropylmethyl-2 '-9/3-dihydroxy-5-methyl-6,7- benzomorphan 2-( 3-nicotinoate-N-oxide) Substitution in the procedure of Example 47 for the 4-nicotinoyl chloride hydrochloride used therein of an equimolar quantity of 3-nicotinoyl chloride-N-oxide produces the desired title ester.

EXAMPLE 49 2'-Monomethoxymethyl ether of l-2-cyclopropylmethyl-2-9B-dihydroxy-5-methyl 6,7- benzomorphan Chloromethylmethylether (0.01 mole) is placed into l0 ml of dry dimethylformamide and the resulting solution is added to 0.0075 mole of compound I-Xllc free base dissolved in 20 ml of dry dimethylformamide. Anhydrous sodium carbonate (0.01 l mole) as a fine powder is added to the solution with stirring at about room temperature. Stirring is continued for about 5 hours. The solution is filtered from the sodium carbonate, evaporated to dryness in vacuo to produce the essentially pure title product.

EXAMPLE 50 2-Allyl-9B-hydroxy-2 '-methoxy5-methyl-6,7- benzomorphan hydrobromide (Xle) wherein R is selected from the group consisting of 6 cH -G -R and 1 in which R is H or CH R is selected from the group consisting of H (lower) alkyl. (lower)alkanoyl,

O O R a a- 0 0 O a f' I ll C- O N-Cll -Cil, CH C C UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION 3,891,657 June 24, 1975 Patent No. Dated lnv Ivo Monkovic et a1.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Add inventor Yvon Lambert, Catherine, Canada Signed and Scaled this second Day Of December l975 [SEAL] Arrest:

RUTH C. MASON C. MARSHALL DANN mtrsrmg Officer (mnmlssimu'r uj'fatenrs and Trademarks 

1. A COMPOUND HAVING THE FORMULA
 2. The compound of claim 1 wherein R3 is methyl, R2 is H, and R1 is cyclobutylmethyl; or an acid addition salt thereof.
 3. The compound of claim 1 wherein R2 and R3 are H, and R1 is cyclopropylmethyl; or an acid addition salt thereof.
 4. The essentially pure levorotatory isomer of the compound of claim
 2. 5. The essentially pure levorotatory isomer of the compound of claim
 3. 6. The hydrochloride salts of the compounds of claim
 1. 